Phase 1 adaptive dose-finding study of neoadjuvant gemcitabine combined with radiation therapy for patients with high-risk extremity and trunk soft tissue sarcoma

William W. Tseng, Shouhao Zhou, Christina A. To, Peter F. Thall, Alexander J. Lazar, Raphael E. Pollock, Patrick P. Lin, Janice N. Cormier, Valerae O. Lewis, Barry W. Feig, Kelly K. Hunt, Matthew Ballo, Shreyaskumar Patel, Peter W.T. Pisters

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Abstract

BACKGROUND This study was performed to determine the maximum tolerated dose (MTD) of gemcitabine given concurrently with preoperative, fixed-dose external-beam radiation therapy (EBRT) for patients with resectable, high-risk extremity and trunk soft tissue sarcoma (STS). METHODS Gemcitabine was administered on days 1, 8, 22, 29, 43, and 50 with EBRT (50 Gy in 25 fractions over 5 weeks). The gemcitabine MTD was determined with a toxicity severity weight method (TSWM) incorporating 6 toxicity types. The TSWM is a Bayesian procedure that choses each cohort's dose to have a posterior mean total toxicity burden closest to a predetermined clinician-defined target. Clinicopathologic and outcome data were also collected. RESULTS Thirty-six patients completed the study. According to the TSWM, the gemcitabine MTD was 700 mg/m2. At this dose level, 4 patients (24%) experienced grade 4 toxicity; no toxicity-related deaths occurred. All tumors were resected with microscopically negative margins. Pathologic responses of >90% tumor necrosis were achieved in 17 patients (47%); 14 (39%) had complete responses. With a median follow-up of 6.2 years, the 5-year locoregional recurrence-free survival, distant metastasis-free survival, and overall survival rates were 85%, 80%, and 86%, respectively. CONCLUSIONS The TSWM combines data from qualitatively different toxicities and can be used to determine the MTD for a drug given as part of a multimodality treatment. Neoadjuvant gemcitabine plus radiation therapy is feasible and safe in patients with high-risk extremity and trunk STS. Major pathologic responses can be achieved, and after complete resection, long-term clinical outcomes are encouraging.

Original languageEnglish (US)
Pages (from-to)3659-3667
Number of pages9
JournalCancer
Volume121
Issue number20
DOIs
StatePublished - Oct 1 2015

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gemcitabine
Sarcoma
Maximum Tolerated Dose
Radiotherapy
Extremities
Weights and Measures
Survival
Neoplasms
Necrosis
Survival Rate
Neoplasm Metastasis
Recurrence

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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Phase 1 adaptive dose-finding study of neoadjuvant gemcitabine combined with radiation therapy for patients with high-risk extremity and trunk soft tissue sarcoma. / Tseng, William W.; Zhou, Shouhao; To, Christina A.; Thall, Peter F.; Lazar, Alexander J.; Pollock, Raphael E.; Lin, Patrick P.; Cormier, Janice N.; Lewis, Valerae O.; Feig, Barry W.; Hunt, Kelly K.; Ballo, Matthew; Patel, Shreyaskumar; Pisters, Peter W.T.

In: Cancer, Vol. 121, No. 20, 01.10.2015, p. 3659-3667.

Research output: Contribution to journalArticle

Tseng, WW, Zhou, S, To, CA, Thall, PF, Lazar, AJ, Pollock, RE, Lin, PP, Cormier, JN, Lewis, VO, Feig, BW, Hunt, KK, Ballo, M, Patel, S & Pisters, PWT 2015, 'Phase 1 adaptive dose-finding study of neoadjuvant gemcitabine combined with radiation therapy for patients with high-risk extremity and trunk soft tissue sarcoma', Cancer, vol. 121, no. 20, pp. 3659-3667. https://doi.org/10.1002/cncr.29544
Tseng, William W. ; Zhou, Shouhao ; To, Christina A. ; Thall, Peter F. ; Lazar, Alexander J. ; Pollock, Raphael E. ; Lin, Patrick P. ; Cormier, Janice N. ; Lewis, Valerae O. ; Feig, Barry W. ; Hunt, Kelly K. ; Ballo, Matthew ; Patel, Shreyaskumar ; Pisters, Peter W.T. / Phase 1 adaptive dose-finding study of neoadjuvant gemcitabine combined with radiation therapy for patients with high-risk extremity and trunk soft tissue sarcoma. In: Cancer. 2015 ; Vol. 121, No. 20. pp. 3659-3667.
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title = "Phase 1 adaptive dose-finding study of neoadjuvant gemcitabine combined with radiation therapy for patients with high-risk extremity and trunk soft tissue sarcoma",
abstract = "BACKGROUND This study was performed to determine the maximum tolerated dose (MTD) of gemcitabine given concurrently with preoperative, fixed-dose external-beam radiation therapy (EBRT) for patients with resectable, high-risk extremity and trunk soft tissue sarcoma (STS). METHODS Gemcitabine was administered on days 1, 8, 22, 29, 43, and 50 with EBRT (50 Gy in 25 fractions over 5 weeks). The gemcitabine MTD was determined with a toxicity severity weight method (TSWM) incorporating 6 toxicity types. The TSWM is a Bayesian procedure that choses each cohort's dose to have a posterior mean total toxicity burden closest to a predetermined clinician-defined target. Clinicopathologic and outcome data were also collected. RESULTS Thirty-six patients completed the study. According to the TSWM, the gemcitabine MTD was 700 mg/m2. At this dose level, 4 patients (24{\%}) experienced grade 4 toxicity; no toxicity-related deaths occurred. All tumors were resected with microscopically negative margins. Pathologic responses of >90{\%} tumor necrosis were achieved in 17 patients (47{\%}); 14 (39{\%}) had complete responses. With a median follow-up of 6.2 years, the 5-year locoregional recurrence-free survival, distant metastasis-free survival, and overall survival rates were 85{\%}, 80{\%}, and 86{\%}, respectively. CONCLUSIONS The TSWM combines data from qualitatively different toxicities and can be used to determine the MTD for a drug given as part of a multimodality treatment. Neoadjuvant gemcitabine plus radiation therapy is feasible and safe in patients with high-risk extremity and trunk STS. Major pathologic responses can be achieved, and after complete resection, long-term clinical outcomes are encouraging.",
author = "Tseng, {William W.} and Shouhao Zhou and To, {Christina A.} and Thall, {Peter F.} and Lazar, {Alexander J.} and Pollock, {Raphael E.} and Lin, {Patrick P.} and Cormier, {Janice N.} and Lewis, {Valerae O.} and Feig, {Barry W.} and Hunt, {Kelly K.} and Matthew Ballo and Shreyaskumar Patel and Pisters, {Peter W.T.}",
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T1 - Phase 1 adaptive dose-finding study of neoadjuvant gemcitabine combined with radiation therapy for patients with high-risk extremity and trunk soft tissue sarcoma

AU - Tseng, William W.

AU - Zhou, Shouhao

AU - To, Christina A.

AU - Thall, Peter F.

AU - Lazar, Alexander J.

AU - Pollock, Raphael E.

AU - Lin, Patrick P.

AU - Cormier, Janice N.

AU - Lewis, Valerae O.

AU - Feig, Barry W.

AU - Hunt, Kelly K.

AU - Ballo, Matthew

AU - Patel, Shreyaskumar

AU - Pisters, Peter W.T.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - BACKGROUND This study was performed to determine the maximum tolerated dose (MTD) of gemcitabine given concurrently with preoperative, fixed-dose external-beam radiation therapy (EBRT) for patients with resectable, high-risk extremity and trunk soft tissue sarcoma (STS). METHODS Gemcitabine was administered on days 1, 8, 22, 29, 43, and 50 with EBRT (50 Gy in 25 fractions over 5 weeks). The gemcitabine MTD was determined with a toxicity severity weight method (TSWM) incorporating 6 toxicity types. The TSWM is a Bayesian procedure that choses each cohort's dose to have a posterior mean total toxicity burden closest to a predetermined clinician-defined target. Clinicopathologic and outcome data were also collected. RESULTS Thirty-six patients completed the study. According to the TSWM, the gemcitabine MTD was 700 mg/m2. At this dose level, 4 patients (24%) experienced grade 4 toxicity; no toxicity-related deaths occurred. All tumors were resected with microscopically negative margins. Pathologic responses of >90% tumor necrosis were achieved in 17 patients (47%); 14 (39%) had complete responses. With a median follow-up of 6.2 years, the 5-year locoregional recurrence-free survival, distant metastasis-free survival, and overall survival rates were 85%, 80%, and 86%, respectively. CONCLUSIONS The TSWM combines data from qualitatively different toxicities and can be used to determine the MTD for a drug given as part of a multimodality treatment. Neoadjuvant gemcitabine plus radiation therapy is feasible and safe in patients with high-risk extremity and trunk STS. Major pathologic responses can be achieved, and after complete resection, long-term clinical outcomes are encouraging.

AB - BACKGROUND This study was performed to determine the maximum tolerated dose (MTD) of gemcitabine given concurrently with preoperative, fixed-dose external-beam radiation therapy (EBRT) for patients with resectable, high-risk extremity and trunk soft tissue sarcoma (STS). METHODS Gemcitabine was administered on days 1, 8, 22, 29, 43, and 50 with EBRT (50 Gy in 25 fractions over 5 weeks). The gemcitabine MTD was determined with a toxicity severity weight method (TSWM) incorporating 6 toxicity types. The TSWM is a Bayesian procedure that choses each cohort's dose to have a posterior mean total toxicity burden closest to a predetermined clinician-defined target. Clinicopathologic and outcome data were also collected. RESULTS Thirty-six patients completed the study. According to the TSWM, the gemcitabine MTD was 700 mg/m2. At this dose level, 4 patients (24%) experienced grade 4 toxicity; no toxicity-related deaths occurred. All tumors were resected with microscopically negative margins. Pathologic responses of >90% tumor necrosis were achieved in 17 patients (47%); 14 (39%) had complete responses. With a median follow-up of 6.2 years, the 5-year locoregional recurrence-free survival, distant metastasis-free survival, and overall survival rates were 85%, 80%, and 86%, respectively. CONCLUSIONS The TSWM combines data from qualitatively different toxicities and can be used to determine the MTD for a drug given as part of a multimodality treatment. Neoadjuvant gemcitabine plus radiation therapy is feasible and safe in patients with high-risk extremity and trunk STS. Major pathologic responses can be achieved, and after complete resection, long-term clinical outcomes are encouraging.

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U2 - 10.1002/cncr.29544

DO - 10.1002/cncr.29544

M3 - Article

VL - 121

SP - 3659

EP - 3667

JO - Cancer

JF - Cancer

SN - 0008-543X

IS - 20

ER -